Alkyl-amino-alkyl para-alkoxybenzoates



Patented June 29, 1948 ALKYL-AMINO -ALKYL PARA- ALKOXY- BENZOATES Walter G. Christiansen, Glen Ridge, and George I 0. Chase, Hawthorne, Squibb & Sons, New York, N.

of New York No Drawing. Continuation N. J assignors to E. B.

Y., a corporation of application Serial No. 353,920, August 23, 1940. This application- .July 20, 1944, Serial No. 545,884

This application is a continuation of Christiansen and Aste application Serial No. 353,920, filed August 23, 1940, now abandoned.

This invention relates to, and has for its object the provision of, certain amino-esters, acid-addition salts thereof, and a method of preparing them. These amino-esters have the general formuia wherein It represents a member of the group consisting of lower alkyl and hydroxy-(lower alkyl) especially lower alkyl, and R1 represents a member of the group consisting of hydrogen and lower alkyl, especially hydrogen,

The subject-matter of this application is related to that of Christiansen and Harris application Serial No. 163,034, filed September 9, 1937, now abandoned, the compounds of the former being N-mono-substituted analogs of the N-di-substituted compounds of the latter.

The compounds of this invention are valuable therapeutic agents, being particularly effective for inducing local anesthesia. They have localanesthetic activities of the same order as the superior local anesthetic diethoxin (fi-diethylaminoethyl p-ethoxy-benzoate hydrochloride), as determined by corneal tests in rabbits (with both aqueous and buffer solutions), intradermal tests in guinea pigs (with both aqueous and buffer solutions), and sciatic nerve block tests (with aqueous solutions). Moreover, these compounds cause i no irritation corneally, and, as determined by tests in mice, have intravenous toxicities significantly lower than that of diethoxin (the compound of Example 2, for instance, having half the intravenous toxicity of diethoxin).

The amino-esters of this invention may be prepared by reacting an aracyl halide of the general iormula (lower alkyl)-(iHOOHl-(halogen) The amino-esters are generally recovered in the form or their acid-addition salts with hydro- 12 Claims. (Cl. 260473) chloric acid; but other acids forming addition salts with amines may be used in place of hydrochloric; for example, boric, nitric, lactic, tartaric, citric, phosphoric, sulfuric, picric, and picrolonic. The addition salts may be converted into the free bases in the usual manner.

,The following examples are illustrative of the invention:

Exsmrn 1 e- [N- (pl-hudrory-ethyl) -a.min0] -ethyl ester of n-butomy-benzoic acid. (hydrochloride) 21.2 g. p-n-butoxy-benzoyl chloride dissolved in 50 cc. dry ether is added dropwise to 31.5 g. diethanolamine vigorously stirred in an equal vol-'- ume of dry ether; and the reaction mixture is refluxed several hours, and, after cooling, is extracted with dilute hydrochloric acid. The aqueous layer is alkalinized with aqueous sodium hydroxide, the liberated base extracted with ether, the extract washed with water until an aliquot of the wash water can be neutralized with a small constant volume of N/lO sulfuric acid, and the dry ether extract treated with ethereal hydrogen chloride to precipitate the hydrochloride. The solid obtained is purified by dissolving in absolute alcohol and precipitating with dry ether. The compound yields a hazy 1% aqueous solution having a pH of 3.80.

EXAMPLE 2 13.8 g. p-ethoxy-benzoyl chloride dissolved in 50 cc. dry ethylene dichloride is treated .with.6.5

g. of ,c-ethylamino-ethanol dissolved in 50 cccdry ethylene dichloride; the reaction mixture is refluxed for 20-30 minutes, and, after cooling, is extracted with dilute hydrochloric acid; theaqueous layer is alkalinized with aqueous sodium hydroxide and the liberated baseextracted with ether. The ethereal sol tion is washed with cc. portions of water until a 10 cc. aliquot requires a small constant volume of N/10 H2804 to neutralize it, and is then dried over K2003, and the hydrochloride precipitated with ethereal hydrogen chloride. The product so obtained weighs 7.8 g. and melts at 153-154" C. After one recrystallization from acetone or a mixture of acetone and alcohol, the melting point is constant at 154-155 C. The compound is a white solid yielding a clear 1% aqueous solution having a pH 0! 5.9.

amino-esters of the general 3 EXAMPLE 3 s-ethylamino-ethyl ester of p-n-butowy-benzoic acid (hydrochloride) This compound is prepared by using p-nbutoxy-benzoyl chloride in place "of p-ethoxybenzoyl chloride in the procedure of Example 2. The compound is a White solid melting at 136 C. and yielding a clear 1% aqueous solution havinga pH of 5.95.

EXAMPLE 4 fi-n-amylamzno-ethyl ester of p-ethoxy-benzoic acid (hydrochloride) This compound is prepared by using fi-n-amylamino-ethanol in place of fl-ethylamino-ethanol in the procedure of Example 2. The compound is a White solid melting at 132.5-133.5 Gland yielding a clear 1% aqueous solution having a pH of 5.9.

EX MPLE 5 fi isobutylaminowthyl ester of p-cthowy-benaoz'c acid (hydrochloride) This compound is prepared by using fi-isobutylamino-ethanol in place of B-ethylamino-ethanol in. the procedure of Example 2. The compound is a White solid melting at 185-'-186 C. and yielding a clear 1% aqueous solution having a pH of 5.95.

.. Manifestly, a variety of other amino-esters. and

acid-additionlsalts thereof embraced by the general formula given hereinbefore may be obtained by reacting the appropriate aracyl halide with the appropriate amino-alcohol. In addition to those, used in the foregoing examples, the utilizable, aracyl halidesinclude, inter alia:

pnvpropoxy-benzoyl chloride p-isopropoxy-benzoyl chloride p-allyloxy-benzoyl chloride.

p-isoamyloxy-benzoyl chloride In addition to those used ample-s, the utilizable inter alia:

in the foregoing examine-alcohols include,

2-ethylamino-cyclohexanol 4-ethylan1ino-2i-butanol The invention may be variously otherwise embodied, within the scope of the appended claims.

We claim:

1. A compound of the group consisting of:

formula wherein R represents a member'of the group consisting of hydrogen and lower alkyl; and acidaddition salts thereof;

2-. Anacid-addition salt of an amino -ester of the-general formula H O 0-(alkrlene) N I (lower alkyl) An acid-addition salt of anamino-ester of hee neral'r rmuiav (lower alkyl) 'where R-is an alkyl radical containing from 2 to fi'carbons' and Z is a primary alkyl radical containing. from 2 to 5 carbons.

8. As new products, salts of the alkoXy-benzoic acid. esters of claim '7.

.9. 'As new products, alkoxybenzoic acid ester hydrochlorides of the structure o oo CHiOHzNHZ-HCl where R. is an alkyl radical containing from 2 to 5 carbons and Z is a primary alkyl radical containing from 2 to 5 carbons.

10. As new products, compounds of the struc ture COOCHaOHzNHZ where R is a lower alltyl radical and'Z is a primary lower alkyl radical.

11. As new products; salts of the alkoxyb'enzoic acid esters of claim 10.

12. As new products, alkoxybenzoic acid ester hydrochlorides of the structure Where R is a lower alkyl' radical and .Z is a primary lower alkyl radical. 1

WALTER G. CHRISTIANSEN. GEORGE O. CHASE.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS ,Numher Name, Date.

1,193,650 Wildman Aug. 8, 1916 2,081,712 May 25, 1937 Rohmann 

